The studies which are outlined in this proposal represent a very exciting and ambitious plan to address the issues of the magnitude, fine specificity, and precise nature of the autoreactive T cell response in MS and further explore the potential contribution of clonally expanded CSF B cells to disease pathogenesis. Using highly innovative approaches we plan to characterize these responses at a single cell level and analyze the TCR usage and CSF B cell repertoire, specifically in the context of various therapeutic interventions. These studies will determine the effectiveness of immune reconstitution with respect to the response to myelin antigens and compare that with what happens to the immune response following more standard immune suppression using mitoxantrone. We will also be able to compare this information with the data we are generating on patients with RRMS receiving more standard immunomodulatory therapies. We anticipate that these studies will provide important information with regard to the immunopathogenesis of MS. Data from these studies will allow the PI to design clinical trials testing novel therapeutic agents for MS based on the translational studies. In addition, the proposed Award will allow the PI to concentrate his efforts on mentoring the next generation of clinician scientists focusing their efforts on multiple sclerosis. [unreadable] [unreadable]